A variety of evidence suggests serotonin 1A (5-HT1A) receptor function is abnormal in panic disorder (PD), posttraumatic stress disorder (PTSD), and depression. This project investigates the pharmacological basis for 5-HT1A abnormalities in vivo by applying positron emission tomography (PET) and the 5-HT1A receptor radioligand F-18FC-WAY100635 to assess 5-HT1A binding potential in PD, PTSD, and unipolar and bipolar depression. Because central 5-HT1A receptor density is down-regulated in rodents by corticosterone administration and by stress-mediated corticosterone secretion, assessments of HPA-axis activity were assessed to determine whether down-regulation of 5-HT1A receptors correlates with cortisol hypersecretion in PD, PTSD, and MDD. PET images of 5-HT1A binding were acquired in subjects who are unmedicated PD, PTSD and depressed patients, or are healthy volunteers. The 5-HT1A receptor volume of distribution was calculated with a two tissue compartment model of PET data after a bolus infusion of (F-18FCWAY). The 5-HT1A receptor volume of distribution in the hippocampus, amygdala, ventral ACC, and orbital cortex were compared between the depressive and control samples. The relationships between 5-HT1A receptor volume of distribution and salivary cortisol and between 5-HT1A receptor volume of distribution and cerebrospinal fluid concentrations of corticotrophin releasing hormone (CRH) were assessed by linear regression analysis. During the past year, we completed the analysis of the image data obtained in subjects with MDD and BD entered into this study for 5HT1A receptor imaging, who also were rescanned following mood stabilizer treatment. We are preparing three manuscripts that will describe the results of these studies, and have presented the data at international scientific meetings. The results show prominent reductions in 5HT1A receptor binding in the anterior and posterior cingulate cortices and the insula in bipolar disorder. The 5HT1A receptors in these regions play important roles in regulating emotional behavior. During the upcoming year the effects of serotonin transporter gene polymorphisms on this response will be characterized. In addition, the neuropsychological assessments from this study comparing depressed and healthy subjects have shown deficits in the unmedicated unipolar and bipolar depressed patients that are consistent with dysfunction of the amygdala, ventral anterior cingulate cortex, and orbital cortex. Specifically, unmedicated depressed patients displayed deficits in inhibiting inappropriate responses to affective stimuli that was not present in the healthy control sample suggesting an attentional bias towards these stimuli. In addition, imaging with the serotonin transporter radioligand progressed to permit characterization of the presynaptic portion of the serotonin system. We completed the studies of subjects with unipolar depression, subjects with bipolar depression and healthy controls. These results showed for the first time a marked reduction in 5HTT sites in the brainstem and an increase in 5HTT binding in the thalamus and anterior cingulate in both bipolar depression and unipolar depression. The unipolar and bipolar depressives differed, however, in the brainstem raphe, where 5-HTT binding in the BD sample was lower than that in both the MDD and control samples. A manuscript describing these results has been published and another prepared for publication. Moreover, we have continued to characterize the relationship between ovarian steroids and 5HTT and 5HT1A receptor binding in women who develop post partum depression and menstrual related mood disorders. These data have shown that the imaging measures are sensitive to ovarian steroids. This work is being conducted in collaboration with Dr. Peter Schmidt at NIMH and with Drs. Eydie Moses and Walter Kaye at University of Pittsburgh. Finally we have initiated a study of Cushing's Disease, in which cortisol is oversecreted and in which a high rate of depression ensues. We have imaged 4 subjects to date, and have two other subjects scheduled. This study will be important because it will be able to establish whether cortisol hypersecretion reduced 5HT1A receptors (as suggested by our results in unipolar depression and the results of preclinical studies in rodents) and whether the incidence and severity of depression in Cushing's Disease is related to the effect on 5HT1A receptors.